AMD3465, a novel CXCR4 receptor antagonist, abrogates schistosomal antigen-elicited (type-2) pulmonary granuloma formation.

Abstract

CXCR4 is a major receptor for CXCL12 and is known to participate in multiple physiological systems. The present study tested a second generation CXCR4 antagonist, AMD3465, for effects on highly defined models of Th1- and Th2-cell-mediated hypersensitivity-type pulmonary granuloma formation. Type-1 and type-2 granulomas were induced, respectively, by intravenous challenge of sensitized CBA/J mice with Mycobacteria bovis purified protein derivative- or Schistosoma mansoni egg antigen-coated beads. Before challenge, mice were implanted with osmotic pumps releasing AMD3465 at 5 microg/hour (6 mg/kg/day). Compared to vehicle, AMD3465 had minimal effect on type-1 inflammation or cytokine responses in draining lymph nodes, but the type-2 inflammation was significantly abrogated with reductions in lesion size and eosinophil content as well as abrogated interleukin (IL)-5, IL-10, and IL-13 cytokine production in draining lymph nodes. The biased effect of AMD3465 correlated with greater CXCR4 ligand expression in the type-2 model. Treatment during a primary response impaired lymph node IL-2 production after both Mycobacteria bovis purified protein derivative and Schistosoma mansoni egg antigen challenge indicating an unbiased effect during immune induction. In summary, CXCR4 blockade inhibited eosinophil recruitment during type-2 granuloma formation and interfered with primary and secondary T-cell activation events in lymphoid tissue, suggesting potential therapeutic application for chronic hypersensitivity diseases.

• Authors: Jerry S Hu, Christine M Freeman, Valerie R Stolberg, Bo Chin Chiu, Gary J Bridger, Simon P Fricker, Nicholas W Lukacs, Stephen W Chensue
• Journal: The American journal of pathology (Am J Pathol) Vol. 169 Issue 2 Pg. 424-32 (Aug 2006) ISSN: 0002-9440 [Print] United States
• PMID: 16877345 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, Helminth
• Chemokine CXCL12
• Chemokines, CXC
• Cxcl12 protein, mouse
• Cytokines
• Interleukin-2
• N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine
• Pyridines
• RNA, Messenger
• Receptors, CXCR4

Topics

• Animals
• Antigens, Helminth (immunology)
• Cells, Cultured
• Chemokine CXCL12
• Chemokines, CXC (genetics)
• Cytokines (biosynthesis)
• Dose-Response Relationship, Drug
• Eosinophils (immunology)
• Female
• Gene Expression Regulation (drug effects)
• Granuloma, Respiratory Tract (chemically induced, pathology)
• Interleukin-2 (biosynthesis)
• Lung (drug effects, pathology)
• Lymph Nodes (drug effects)
• Mice
• Pyridines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Receptors, CXCR4 (antagonists & inhibitors, genetics)
• Schistosoma mansoni (immunology)
• Th2 Cells (drug effects)